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Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects
Susan W Robinson1, Cynthia D Morris, Elizabeth Goldmuntz
1Division of Endocrinology, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
Insights
CRELD1 gene mutations are linked to atrioventricular septal defects (AVSD) in individuals without Down syndrome. This discovery offers new insights into the causes of isolated AVSD and heterotaxy syndrome.
Area of Science:
- Genetics
- Cardiology
- Developmental Biology
Background:
- Atrioventricular septal defects (AVSD) are prevalent congenital heart conditions, affecting approximately 3.5 per 10,000 births.
- While often linked to trisomy 21, autosomal dominant forms of AVSD also exist.
- The genetic underpinnings of isolated AVSD and AVSD associated with heterotaxy syndrome remain incompletely understood.
Purpose of the Study:
- To investigate the role of the CRELD1 gene in the pathogenesis of non-trisomy 21-associated atrioventricular septal defects.
- To identify genetic mutations in CRELD1 that contribute to isolated AVSD and AVSD with heterotaxy syndrome.
Main Methods:
- Genetic analysis of the CRELD1 gene in patients with non-trisomy 21-associated AVSD.
- Characterization of identified CRELD1 mutations and their association with specific cardiac malformations.
Main Results:
- Heterozygous missense mutations in the CRELD1 gene were identified in approximately 6% of individuals with non-trisomy 21-associated AVSD.
- These mutations were found in both isolated AVSD cases and those associated with heterotaxy syndrome.
- CRELD1 is implicated as the first human gene linked to the pathogenesis of isolated AVSD and AVSD in heterotaxy.
Conclusions:
- The CRELD1 gene plays a significant role in the development of atrioventricular septal defects, particularly in non-trisomy 21 cases.
- Identification of CRELD1 mutations provides crucial insights into the molecular mechanisms underlying isolated AVSD and heterotaxy syndrome.
- This research represents a key advancement in understanding the complex etiology of AVSD.
Abstract:
Atrioventricular septal defects (AVSD) are common cardiovascular malformations, occurring in 3.5/10,000 births. Although frequently associated with trisomy 21, autosomal dominant AVSD has also been described. Recently we identified and characterized the cell adhesion molecule CRELD1 (previously known as "cirrin") as a candidate gene for the AVSD2 locus mapping to chromosome 3p25. Analysis of the CRELD1 gene from individuals with non-trisomy 21-associated AVSD identified heterozygous missense mutations in nearly 6% of this population, including mutations in isolated AVSD and AVSD associated with heterotaxy syndrome. CRELD1 is the first human gene to be implicated in the pathogenesis of isolated AVSD and AVSD in the context of heterotaxy, which provides an important step in unraveling the pathogenesis of AVSD.